Oxazine derivatives

ABSTRACT

IN WHICH Ph and Ph&#39;&#39; are optionally substituted o-phenylene radicals, R1 stands for hydrogen or a radical of aliphatic nature, Ro, Rx&#39;&#39; and Ry each represents hydrogen or lower alkyl, Rz and Rz&#39;&#39; each represents hydrogen, lower alkyl, aralkyl or aryl, or both together stand for a lower alkylene, are useful psychopharmaceuticals.   Compounds of the formula

United States Patent Wilhelm et al.

OXAZINE DERIVATIVES Inventors: Max Wilhelm, Allschwil; Walter Riess, Basel, both of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,

Filed: July 28, 1972 Appl. No.1 276,005

Related US. Application Data Division of Ser, No. 820,319, April 29, 1969.

Foreign Application Priority Data May 16, 1968 Switzerland 7284/68 Mar. 25, 1969 Switzerland 4480/69 US. Cl. 260/244 R, 260/243 B, 260/247, 260/247.2 B, 260/247.7 F, 260/268 PC, 260/293.62, 260/326.3, 260/326.5 C, 260/326.87, 260/488 CD, 260/562 P, 260/570.6, 260/570.7, 260/570.8 TC, 260/570.9, 260/592, 424/246, 424/248, 424/250, 424/267, 424/274, 424/330 Int. Cl C07d 87/14 Field of Search 260/244, 75

Davis 260/244 Primary Examinerl-larry l. Moatz' Attorney, Agent, or Firm-Joseph G. Kolodny; Ronald A. Diagnault ABSTRACT Compounds of the formula Rr-N P R P11 in which Ph and Ph' are optionally substituted 0- phenylene radicals, R, stands for hydrogen or a radical of aliphatic nature, R,,, R, and R, each represents hydrogen or lower alkyl, R and R each represents hydrogen, lower alkyl, aralkyl or aryl, or both together stand for a lower alkylene, are useful psychopharmaceuticals.

4 Claims, No Drawings ()XAZINE DERIVATIVES CROSS-REFERENC E TO RELATED APPLICATION This is a division of co-pending application Ser. No. 820,319, filed April 29, 1969.

SUMMARY OF THE DISCLOSURE The present invention relates to new aminoalkylethano-anthracenes. Especially it concerns N- substituted 9-(amino-alkyl)-9,l0-dihydro-9,10-ethanoanthracenes containing the nucleus of the formula and containing a free or acylated hydroxyl group or an oxo group in position 12, and their salts.

The N-substituted aminoalkyl radical in position 9 is preferably an N-substituted amino-lower alkyl radical in which the alkylene radical connecting the substituted amino group with the anthracene nucleus is especially a lower linear or branched alkylene radical preferably containing one to four carbon atoms, for example the methylene, ethylene-(1,2), ethylidene, propylene-(1,2), propylene-(1,3), propylidene, butylidene, butylene-( 1,2), butylene-( 1,3), butylene-(2,3) or butylene-( 1,4) radical.

The amino group of the N-substituted aminoalkyl radical may be secondary or tertiary; preferably, it is an aliphatic amino group, that is to say an amino group containing one or two radicals of aliphatic nature. As radicals of aliphatic nature there come into consideration those whose first carbon atom linked with the nitrogen atom is not a member of an aromatic system. Thus, there may be mentioned as substituents of a secondary or tertiary amino group: Lower hydrocarbon radicals of aliphatic nature whose carbon chain may be interrupted by hetero atoms, such asoxygen, sulfur or nitrogen atoms, and/or substituted by hydroxyl group. Lower hydrocarbon radicals of aliphatic nature suitable as substituents of the amino groups are especially such as contain at most eight carbon atoms, being alkyl, alkenyl, alkylene, alkinyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl or cycloalkyl-alkenyl radicals or cycloalkenyl-alkyl or cycloakenyl-alkenyl radicals, aralkyl or aralkenyl radicals, for example phenyllower alkyl or phenyl-lower alkenyl radicals, for example a benzyl, phenylethyl or cinnamyl group which may be substituted for instance by lower alkyl groups, lower alkoxy groups, halogen atoms, trifluoromethyl and/or nitro groups. Radicals of this kind interrupted by hetero atoms are especially oxaalkyl, oxaalkylene, azaalkylene or thiaalkylene radicals. As substituents of the amino group there may be specially mentioned methyl, ethyl, allyl, propyl, isopropyl, methallyl, propargyl radicals; linear or branched butyl, pentyl, hexyl or heptyl radicals linked in any desired position; 3-oxabutyl, 3- oxapentyl, 3-oxaheptyl, 2-hydroxyethyl, 3- hydroxypropyl, butylene-( 1,4), pentylene-(l,5), hexylene-( 1,5), hexylene-( 1,6), hexylene-(2,5), heptylene- (1,7), heptylene-(2,7), heptylene-(2,6), 3-oxapentylene-( 1,5), 3-thiapentylene-( 1,5), 2,4-dimethyl-3-thiapentylene-( 1,5 3-azapentylene-( 1 ,5 3-lower alkyl-3-azapentylene-(1,5) such as 3-methyl-3-azapentylene-( 1,5), 3-(hydroxy-lower alkyl)-3-azapentylene- (1,5) such as 3-(B-hydroxyethyl)-3-azapentylene- 1,5), 3-oxahexylene(l ,6) or 3-azahyxylene-( 1,6) radicals; possibly lower alkylated, such as methylated, cyclopropyl, cyclopentyl or cyclohexyl radicals, or cyclopropyl-, cyclopentylor cyclohexyl-methyl or -ethyl radicals.

The substituted amino group is especially a monoor di-lower alkylamino group such as a methyl-, ethyl-, propyl-, butyl-, isopropyl-, secondary butyl-, dimethyl-, diethyl-, N-methyl-N-ethyl-, dipropyl-, diisopropyl-, dibutyl-, disecondary butylor di-amyl-amino group or a optionally C-lower alkylated and/or in the ring [3 mono-unsaturated pyrrolidino or piperidino group or a optionally C-lower alkylated piperazino, N'-lower alkyl-' or N-(hydroxy-lower alkyl)-piperazino, thiomorpholino or morpholino group.

Acylated hydroxyl groups are hydroxyl groups substituted by carboxylic acid radicals, for example by aliphatic or aromatic carboxylic acid radicals, such as for example hydroxyl groups esterified by benzoic acids, such as the benzoyloxy group or especially lower alkanoyloxy groups, primarily those having six carbon atoms, such as the propionyloxy, butyryloxy, caproyloxy or in the first place the acetoxy group.

The new compounds may contain further substituents. Inter alia, they may contain, for example on the aromatic rings (positions 1 to 8) lower alkyl groups, lower alkoxy groups, halogen atoms, trifluoromethyl groups and/or nitro groups, and each of the two nuclei (positions 1 to 4, and 5 to 8) contains advantageously no more than two, preferably no more than one of the said substituents.

Furthermore, the new compounds may be substituted in position 1 l or 12. Suitable substituents are primarily lower alkyl radicals, especially methyl radicals.

A lower alkyl radical on a carbon atom is especially an alkyl radical containing one to six carbon atoms, for example a methyl, ethyl, propyl or isopropyl radical or a linear or branched butyl, pentyl or hexyl radical linked in any desired position.

Lower alkoxy groups are especially those containing no more than six carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy or butoxy groups. Especially suitable halogen atoms are fluorine, chlorine or bromine atoms.

The new compounds possess valuable pharmacological properties, especially a psychotropic activity. As can be shown in animal tests, for example on mice, on oral administration in doses or 30 to mg/kg, they inhibit the psychomotor excitation produced by mescaline. The new compounds are, therefore, useful as psychopharmaceuticals. The new compounds are also valuable intermediates for the manufacture of other useful substances, especially of pharmacologically active compounds.

Special mention deserve the compounds of the formula elk-R0 and the compounds of the formula I in which R represents a lower alkanoyl radical, for example the acetyl radical, or primarily a hydrogen atom, alk represents a lower alkylene radical containing one to three carbon atoms, especially the radical of the formula -(CH (where n l, 2 or 3), R represents a monoor di-lower alkylamino group, especially a monoor di-methylamino group, a benzylamino group, a piperidino or pyrrolidino group optionally B-monounsaturated in the ring and/or C-lower alkylated; or a optionally C-lower alkylated morpholino, thiomorpholino, piperazino, N'-lower alkylpiperazino or N'- (hydroxy-lower alkyl)-piperazino group such as an N- methylor N-(B-hydroxyethyl)-piperazino group, and R, and R may be identical or different and are lower alkyl or lower alkoxy groups, especially methoxy, halogen atoms, especially chlorine, nitro groups or preferably hydrogen atoms, and more especially 9-('ydimethylaminopropyl l 2-oxo-9, l0-dihydro-9, l0- ethano-anthracene, 9 (y-methylamino-propyl l 2-oxo- 9,10-dihydro-9,lO-ethano-anthracene, and primariyl 9-( dimethylaminomethyl l2-acetoxy-9, IO-dihydro- 9,10-ethanoanthracene which, for example on oral administration of a dose of 30 mg/kg produces in the mouse a distinct mescaline-antagonistic effect.

The new compounds are manufactured by known methods.

Preferably, in a 9,l0-dihydro-9,10-ethanoanthracene that contains in position 12 a free or acylated hydroxyl group or an oxo group and in position 9 a radical X convertible into an N-substituted aminoalkyl group, X is converted into an N-substituted aminoalkyl radical.

A radical X convertible into an N-substituted aminoalkyl group is, for example, a corresponding radical which differs from the desired aminoalkyl radical in that it contains a double bond extending from the nitrogen atom to a vicinal carbon atom'(in' which case the said carbon atom carries one hydrogen atom fewer). Such radicals are, for example, corresponding N- substituted aminoor immonium-alkyl groups in which one substituent is linked through a double bond with the nitrogen atom of the amino group.

The conversion of the said radicals into an aminoalkyl group is carried out, for example, by reduction of the double bond. The reduction is performed in the usual manner, for example with hydrogen in the presence of a platinum, palladium or nickel catalyst. Shiffs bases can also be reduced by means of sodium borohydride or lithium-aluminium hydride. Azomethine bonds may also be reduced with formic acid. The reduction is advantageously performed in a solvent, for example in an organic solvent. The catalytic reduction is carried out, for example, with the use of a lower alkanol such as methanol or ethanol as solvent.

A further radical X convertible into an N-substituted amino-alkyl group is, for example, a corresponding radical that differs from the desired aminoalkyl radical in that it carries an oxo group on at least one carbon atom vicinal to a nitrogen atom or an optionally further N-' substituted aminoalkyl radical, whose nitrogen atom carries an esterified carboxyl group, such as, for example a carbalkoxy group or an aralkoxy-carbonyl group in which the alkyl and aralkyl radicals are, for example, those mentioned above. Such radicals are more especially corresponding N-substituted carbamyl or carbamylalkyl radicals, corresponding acylaminoalkyl radicals or carbalkoxyaminoalkyl radicals. These radicals are converted into an N-substituted aminoalkyl group by reducing the 0x0 group to hydrogen atoms or by reducing the esterified carboxyl group to the methyl group, respectively.

The reduction is carried out in the usual manner, for example with an amide reducing agent, above all with lithium-aluminum hydride.

Another radical X convertible into an N-substituted aminoalkyl group is, for example, an N-unsubstituted aminoalkyl group. The conversion of this radical into the N-substituted aminoalkyl group is carried out, for example, by substitution, for instance with one of the substituents mentioned above for the amino group, especially by reaction with a reactive ester of a suitable alcohol or with a 1,2-epoxide, for example ethylene oxide. Reactive esters suitable for this purpose are in the first place esters with hydrohalic acids such as hydrochloric, hydrobromic or hydriodic acid, with sulfuric acid or with aryl-sulfonic acids such as benzenesulfonic, p-bromobenzene-sulfonic or p-toluene-sulfonic acid.

The reaction is carried out in the usual manner, advantageously in the presence of a solvent and, for example, in the presence of a condensing agent such as a basic condensing agent, at room temperature or with heating or cooling.

Another radical convertible into an N-monosubstituted aminoalkyl group is, for example, an N- mono-substituted aminoalkyl group which'contains on the nitrogen atom additionally an eliminable radical Y. The conversion into the N-mono-substituted aminoalkyl group is achieved, for example, by elimination of the radical Y.

An eliminable radical is for example, a radical eliminable by hydrolysis or reduction. The elimination is effected in the usual manner, for example by hydrolysis or reduction.

A radical eliminable by hydrolysis is, for example, an acyl radical, especially an alkanoyl radical, in the first place a lower alkanoyl radical, such as acetyl, benzoyl,

phenylalkanoyl, carbalkoxy, for example the tertiary butoxycarbonyl, carbethoxy or carbomethoxy radical, or an a-aralkoxycarbonyl radical, for instance a carbobenzoxy radical. The hydrolytic elimination of the radical elminable by hydrolysis may be carried out in the usual manner, for example with a hydrolyzing agent, for example in the presence of an acid agent, for instance a dilute mineral acid such as sulfuric or a hydrohalic acid, or preferably in the presence of a basic agent, for example an alkali metal hydroxide such as sodium hydroxide.

A radical eliminable by reduction is, for example, an acyl radical eliminable by reduction, for instance an a-aralkoxycarbonyl radical such as a carbobenzoxy radical, which can be eliminated, for example, by hydrogenolysis, for instance by reduction with catalytically activated hydrogen, such as hydrogen in the presence of a hydrogenating catalyst, such as a palladium or platinum catalyst.

When the starting material used in those of the processes mentioned above, in which the conversion into the N-substituted aminoalkyl group is performed by reduction or hydrogenolysis, is a l2-oxo compound, it is possible depending on the type of reducing agent used to reduce the oxo group at the same time to the hydroxyl group. If in such a case it is desired to obtain the oxo compound, the resulting hydroxyl group may be reoxidized to the oxo group, for example as described below.

When the starting material is a compound with an acyloxy group in l2-position and the reducing agent is lithiumaluminum hydride or a similar reducing agent, the l2-acyloxy group can simultaneously be reduced to the hydroxyl group. If in this case an acyloxy group is desired, the resulting l2-hydroxy group may be acylated, for example as described below.

The new compounds in which the N-substituted aminoalkyl radical is an optionally substituted 1- aminoalkyl radical and which contain in l2-position a free hydroxyl group, can also be obtained when in a corresponding 6, 1 1,3 ,4-tetrahydro-6', l O-methano-spiro[anthracene- 9( 10H), 5'(2'H)[1,3]oxazine] the oxazine ring is split up by reduction.

The reductive cleavage is performed in per se conventional manner for example with hydrogen in the presence of a hydrogenation catalyst, for example a platinum, palladium or nickel catalyst, by means of a metal amalgam, such as sodium amalgam, or by means of a di-light metal hydride, such as for example sodium borohydride or lithium-aluminum hydride. Formic acid can likewise be used. The reduction is perferably performed in a solvent, for example an organic solvent. For the catalytic reduction there is used, for example, a lower alkanol, such as methanol or ethanol, as solvent. When formic acid is used as reducing agent, it is preferable to work under hydrolyzing conditions, such as an excess of water.

Substituents in resulting compounds may be introduced, modified or eliminated within the framework of the final products.

Thus, for example, in a resulting l2-hydroxy com pound the hydroxyl group may be oxidized to the oxo group.

The oxidation is carried out in the usual manner, for example by treatment with an oxidant, for example a chromium trioxide compound, such as chromic acid or chromium trioxidepyridine, a hypohalite such as tertiary butylhypochlorite, a copper-(ll)-salt, for example copper sulfate, bismuth oxide, or for instance by the Oppenauer method, for example by treatment with a ketone such as a lower alkanone, for example acetone, a cycloalkanone such as cyclohexanone or a quinone, in the presence of asuitable catalyst such as a metal salt, especially an aluminum salt, of branched lower alkanols, such as aluminum tertiary butylate or aluminum isopropylate or an aluminum phenolate.

In a resulting l2-oxo compound the oxo group may be reduced in the usual manner to the hydroxyl group.

The reduction is carried out in the usual manner, for example by metallic reduction, such as treatment with sodium in ethanol, or with a complex metal hydride such as sodium borohydride, or with catalytically activated hydrogen, for example hydrogen in the presence of a platinum, palladium, nickel or copper catalyst, such as platinum oxide, palladium carbon, Raney nickel or copper chromite. The reaction is preferably performed in the presence of a diluent and/or solvent, at

room temperature or with cooling or heating, under atmospheric or superatmospheric pressure. I

The oxo group may also be reduced by the Meerwein-Ponndorf-Verley method. For example, the oxo compound may be treated in the usual manner in a lower alkanol, such as isopropanol, in the presence of a suitable alkanolate, such as aluminum isopropylate.

ether or tetrahydrofuran. The metal salt so obtained is then hydrolyzed in the usual manner, for example by the addition of water or ammonium halide, to the free hydroxy compound.

Resulting l2-acyloxy compounds can be converted in the usual manner into the corresponding l2-hydroxy compounds, for example by hydrolysis, for example in the-presence of acid catalysts, such as mineral acids, or basic catalysts, such as alkali metal hydroxides, for example sodium hydroxide solution.

When the amino group is at most monosubstituted, that is to say, for example an N-monosubstituted laminoalkyl group, such as an aminomethyl group, acyl migration may take place during such hydrolysis, in that the acyl radical first moves to the nitrogen atom and is then split off during a later stage of the hydrolysis.

Alternatively, resulting l2-acyloxy compounds can be converted into l2-hydroxy compounds by reduction. Reduction to the free hydroxyl group is performed in the usual manner, for example with an ester reducing agent, such as sodium in a lower alkanol, a di-light metal hydride, such as lithiumaluminum hydride.

Resulting l2-hydroxyl compounds can be acylated in the usual manner, for example by reaction with a halide or anhydride of a corresponding carboxylic acid.

Furthermore, for example, in compounds in which the amino group of the aminoalkyl group is a secondary amino group or an N'-unsubstituted piperazino group, substituents may be introduced, for instance as described above for the substitution of the primary amino group, especiallyby reaction with a reactive ester, for example one of those mentioned above, of a corresponding alcohol or with a 1,2-epoxide.

In a resulting final product that carries on the amino group of the aminoalkyl radical a hydrogenolytically eliminable radical, such as an a-aralkyl radical, for example a benzyl group, this radical may be eliminated by a known method, for example as described above for a-aralkoxycarbonyl radicals.

These subsequent conversions can be performed separately or jointly and in any desired order of successron.

aminosalicylic Depending on the starting materials and reaction conditions used the final products are obtained in free form or in form of their salts which are likewise intaric, citric, ascorbic, maleic, hydroxymaleic, or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or pacid, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethlenesulfonic acid; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid; methionine, tryptophan,

lysine or arginine.

These or other salts of the new compounds, for example their picrates or perchlorates, may also be used for purifying the resulting free bases by converting them into their salts, isolating the salts and liberating the bases again from them. In view ofthe close relationship between the new compounds in the free form and in the form of their salts, what has been said above and hereinafter referring to the bases concerns also the corresponding salts wherever this is possible and useful.

The invention includes also any variant of the present process in which an intermediate obtainable at any stage thereof is used as a starting material and any remaining process step(s) is/are carried out or in which a starting material is formed under the reaction conditions or used in form of a salt.

Thus, a 9-(oxoalkyl)-9,lO-dihydro-9,l0-ethanoanthracene which contains in l2-position an oxo group or primarily a free or acylated hydroxyl group can be reacted with a primary or secondary amine, for example in the presence of hydrogen and of a hydrogenation catalyst, or an N-unsubstituted or N-monosubstituted 9-(aminoalkyl )-9, l -dihydro-9, l O-ethanoanthracene which in l2-position carries a free or acylated hydroxyl group or an oxo group can be reacted with an aldehyde or a ketone under reducing conditions, for example those mentioned above. There is thus intermediately formed a 9,l0-dihydro-9,IO-eIhano-anthracene which carries in l2-position a free or acylated hydroxyl group or an oxo group and in 9-position a radical that differs from the desired aminoalkyl radical in that it contains a double bond extending from the nitrogen atom to a vicinal carbon atom (in which case the said carbon atom carries on hydrogen atom fewer), or a corresponding 6',l l,3',4'-tetrahydro-6', l O- methanospirolanthracene-9( l0H),5 (2'H)[ 1,3]- oxazine] which is then reduced according to this invention.

Furthermore, the l2-acyloxy compounds having in 9- position an N-unsubstituted l-aminoalkyl group, especially an N-unsubstituted aminomethyl group, which are required for the substitution, can be made in situ by starting from the corresponding l2-hydroxy-9- (lacylaminoalkyl) compoundand reacting it with the substituting agent. Acyl migration from the nitrogen atom to the oxygen atom takes place intermediately, so

8 that the corresponding 9-( l-aminoalkyl)-l2-acyloxy compound is obtained which is then substituted according to this invention as described above.

If the new compounds contain asymmetric carbon atoms, and depending on the starting materials and reaction conditions used, they may be in form of optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, in form of isomer mixtures (racemate mixtures).

A resulting isomer mixture (racemate mixture) may be resolved into the two stereoisomeric (diastereomeric) pure racemates on the basis of the physicochemical differences between the constituents, for example by chromatography and/or fractional crystallization.

Resulting racemates may be resolved by known methods from example by recrystallization from an optically active solvent, or with the aid of microorganisms or by reaction with an optically active acid capable of forming salts with the racemic compound and isolation of the salts thus obtained, for example on the strength of their different solubilities into the diastereomers from which the antipodes may be liberated by treatment with suitable reagents. Particularly frequently used optically active acids are, for example, the D- and L- forms of tartaric acid, di-o-toluyltartaric, malic, mandelic, camphor-sulfonic or quinic acid. It is advantageous to isolate the more active of the two antipodes.

The reactions of this invention are advantageously performed with the use of starting materials that furnish the groups of final substances specially mentioned above and more particularly the specifically described or emphasized final products.

The 6',l l,3',4'tetrahydro-6', l O-methanospiro[anthracene-9( l0H),5(2'H)-[1,3]oxazines1having the nucleus of the formula are new and also have valuable pharmacological properties, especially a psychotropic acitivity. Apart from a cocaine antagonistic action which can be demonstrated, for example in the mouse, they produce in the first place an inhibition of the psychomotor excitation due to mescaline in animal experiments, for example on oral administration of doses of 30 to mg/kg to mice. Accordingly, they are useful as psychopharmaceuticals and form part of the present invention.

Suitable substituents of the new 6',l l,3,4- tetrahydro-6', 10-methano-spiro[anthracene- 9(10H),5'(2'H)[l,3]oxazines] are primarily those corresponding to the aforementioned substituents. Accordingly, the nitrogen 'atom in 3'-position may carry for example the monovalent substituents mentioned above for the amino group or it may be unsubstituted. Suitable substituents for the 2'-position are primarily lower alkyl radicals, for example those mentioned, or lower alkylene radicals, such as butylene-(1,4)- or pentylene-( l ,5) radicals, or aralkyl or aryl radicals, for example those mentioned above. However, the 2- position is preferably unsubstituted.

Of particular advantage are the compounds of the formula in which R, and R have the meanings given above, R stands for a lower alkyl group, for example one of those mentioned above, primarily methyl, a benzyl radical or a hydrogen atom, and R,, and R each for a lower alkyl radical, for example one of those mentioned, or a hydrogen atom, and especially 3-methyl-6',l l,3',4- tetrahydro-6', 1 O-methano-spiro[anthracene- @(IOHLS'(2'H)[l,3]oxazine] which, for example in the form of its methanesulfonate on-oral administration of a dose of 30 mg/kg to the mouse has a'distinct mescaline-antagoni'stic action; I

The 7 new 6',l l,3'4-tetrahydro-6',l0- methanospiro[anthracene- 9( l0H),5'(2'H)[1,3]oxazines] are prepared by per se conventional methods.

An advantageous procedure consists in closing the oxazine ring in an appropriate N-unsubstituted or N- mono-substituted 9-( aminomethyl l 2-hydroxy-9, l0- dihydro-9,lO-ethano-anthracene by reaction with a corresponding oxo compound, such as an aldehyde or ketone.

C yclization is performed in per se conventional manner, perferably in the presence of a solvent and appropriately in the presence of a condensing agent, for example an acid agent, such as an acid, such as, for example a mineral acid or carboxylic acid, such as formic acid. If necessary, the reaction may be performed in an aromatic hydrocarbon, such as benzene or toluene and the water formed during the reaction distilled off azeotropically.

Resulting oxazines which contain a hydrogen atom in 3'-position can be substituted in the usual manner. The substitution is performed by reaction with a reactive ester or a corresponding alcohol. Reactive esters are primarily esters with hydrohalic acids, such as hydrochloric, hydrobromic, or hydroiodic acid. with sulfuric acid or with arylsulfonic acids, such as benzenesulfonic, para-bromobenzenesulfonic or para-toluenesulfonic acid.

The reaction is performed in the usual manner, advantageously in the presence of a solvent, and for example in the presence of a condensing agent, such as a basic condensing agent, at room temperature or with cooling or heating. I

The substitution can also be performed reductively, for example by reaction with a corresponding oxo compound, such as an aldehyde or ketone, and reduction of the resulting condesnation product. Reducing agents that may be used are, for example, catalytically activated hydrogen, such as hydrogen in the presence of a platinum, palladium or nickel catalyst, or formic acid.

To prevent the oxazine ring being split, hydrolyzing conditions should beavoided, and the reduction, in the case of catalytic hydrogenation, discontinued when the calculated quantity of hydrogen has been absorbed.

Substitution may also take place simultaneously with the closing of'the oxazine ring. Thus, for example, a 9- aminomethyl compound which is unsubstituted at the amino group can be reacted with formic acid and formaldehyde, advantageously while avoiding too large an excess of water, so as to form the oxazine ring and to methylate the the resulting oxazine in 3'-position.

The N-unsubstituted 9-(aminoalkyl)-9,IO-dihydro- 9,10-ethano-anthracenes used as starting materials which contain in position 12 a free or acylated hydroxyl group or an oxo group, are new and likewise possess an antagonistic activity towards cocain and mescalin. Therefore, they are likewise included in this invention; they may be prepared in a similar manner as the corresponding N-substituted compounds, by using as starting material in each case the N-unsubstituted instead of the N-substituted compound. Furthermore, they are also obtained when the radical in 9-position of a corresponding 9-cyano, 9-cyanoalkyl, 9-nitroalkyl or 9- hydroxyiminoalkyl compound is reduced to the N- unsubstituted aminoalkyl radical. The reduction is carried out in the usual manner; nitro groups, for example, may be reduced with nascent hydrogen, for example with a metal, such as iron, and mineral acid, or with zinc and an acid or alkali metal hydroxide, or with catalytically activated hydrogen. Cyano groups may be reduced, for example, with nascent hydrogen, for example with metals, such as sodium in a lower alkanol such as ethanol or butanol, or with catalytically activated hydrogen. Hydroxyiminoalkyl radicals can be hydrogenated, for example, with metal hydrides, for example alkali metal-earth metal hydrides such as alkali metal borohydrides, for example sodium borohydride, or with catalytically activated hydrogen. The catalytic reduction is carried out, for example, with hydrogen in the presence of a metal catalyst, such as a nickel, palladium or platinum catalyst, preferably in an organic solvent such as a lower alkanol, for example methanol or ethanol, or in an amide, for example formamide or dimethylformamide, or glacial acetic acid, if desired, or required in the presence of ammonia.

The 9, l0-dihydro-9, lO-ethano-anthracenes used as starting materials or intermediates, which contain in position 12 a free or acylated hydroxyl group or an oxo group and in position 9 a radical that differs from the desired N-substituted or N-unsubstituted aminoalkyl radical in that it carries an oxo group on at least one carbon atom vicinal to a nitrogen atom, are likewise new and included in this invention. They are obtained, for example, when a corresponding 9-aminoalkyl compound is acylated by means of ahalide, such as the chloride, or an anhydride of a monocarboxylic or dicarboxylic acid, or when a halide, such as the chloride, of a corresponding l2-oxo-, -acyloxyor -hydroxy-9,l0- dihydro9,10 ethano-anthracene-9-carboxylic or 9- alkanecarboxylic acid is reacted with ammonia or with a primary or secondary amine.

The oxazines mentioned and the other amino compounds mentioned which are useful as starting materials are obtained in the free form or as salts, depending on the reaction conditions and starting materials used.

Salts and free compounds can be converted one into the other, for example as described above.

The compounds mentioned which can be used as starting materials may be present as optical antipodes, racemates or mixtures of isomers, depending on whether they contain any asymmetric carbon atoms and how many. If desired, racemates and mixtures of may be used, for example. in the form of pharmaceutical preparations containing them in the free form or in the form of their salts, especially of therapeutically acceptable acid addition salts, in conjunction or admixture with an organic or inorganic, solid or liquid pharmaceutical excipient suitable, for example for enteral, such as oral, or parenteral administration. Suitable excipients are substances that do not react with the new compounds, for example water, gelatin, starches, lactose, stearyl alcohol, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, propyleneglycols, white petroleum jelly or other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees, capsules or suppositories, or in liquid form solutions (for example elixirs or syrups), suspensions or emulsions. They may be sterilized-and- /or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, solubilizers, saltsfor regulating the osmotic pressure or buffers. They may also contain further therapeutically valuable substances. The pharmaceutical preparations are formulated by the usual methods. r

The new compounds may also be used in form of animal feedstuffs or additives to animal feedstuffs using,

for example, the conventional extenders and diluents, and feedstuffs respectively.

The following Examples illustrate the invention.

Example 1 A suspension of 6 g of lithium-aluminum hydride in 200 ml of tetrahydrofuran is dropped at 10C into a solution of 30 g of 9-(acetylaminomethyl)-l2-hydroxy- 9,10-dihydro-9,IO-ethano-anthracene in 200 ml of tetrahydrofuran, and the mixture is refluxed for l hour, then cooled to room temperature, and 12 ml of water in ml of tetrahydrofuran are dropped in. The precipitate formed is filtered off and the filtrate evaporated under vacuum. The residue is dissolved in chloroform and extracted with 200 ml of N-hydrochloric acid. The acid extract is. rendered alkaline with sodium hydroxide solution, and the precipitated base is extracted with chloroform. The chloroform extract is evaporated and furnishes 9-(ethylaminomethyl l 2-hydroxy-9, l 0- dihydro-9,lO-ethano-anthracene of the formula cm-NH-QH,

in crystals which melt at 142C after recrystallization from petroleum ether. The hydrochloride melts at 246C.

The 9-(acetylaminomethyl)- l 2-hydroxy-9, 10- dihydro-9,IO-ethano-anthracene used as starting material may be prepared in the following manner:

A mixture of 100 g of 9-anthraldehyde and 200 g of vinyl acetate in 750 ml of toluene is heated in an autoclave for 24 hours at 200C, then evaporated and the residue is crystallized from ethanol, to yield crystalline 12-acetoxy-9, l0-dihydro-9, l 0-ethano-9-anthraldehyde melting at l38-l40C.

5O Grams of this aldehyde are hydrogenated in a solution of 10 g of ammoniain 1200 ml of ethanol in the presence of 6 g of Raney nickel under a hydrogen pressure of 25 atmospheres (gauge) at 100C. After 17 hours the catalyst is filtered off and the filtrate evaporated to dryness. The residue is dissolved in chloroform and the solution successively extracted with N-sulfuric acid, N-sodium hydroxide solution and with water and evaporated to yield 9-(acetylaminomethyl)- 2- hydroxy-9, l 0-dihydro-9, l Oethano-anthracene which melts at l66l68C on recrystallization from ethylacetate-l-ether.

Example 2 l2 Grams of 9-(N-acetyl-ethylaminomethyl)- l 2- hydroxy-9, l O-dihydro-9, IO-ethano-anthracene in 5 0 ml of tetrahydrofuran are dropped into a suspension of 3 g of lithium-aluminum hydride in 70 ml of tetrahydrofuran and the whole is refluxed for 1 hour and cooled. Then 3 ml of water in 10 ml of tetrahydrofuran are cautiously dropped in and the precipitate formed is filtered off. The filtrate is evaporated under vacuum and the residue dissolved in chloroform and extracted with N- sulfuric acid. The acid extract is rendered alkaline with sodium hydroxide solution and the liberated base extracted with chloroform, to yield 9- (diethylaminomethyl)- l 2-hydroxy-9, l O-dihydro-9, l O- ethano-anthracene of the formula CzHa which melts at ll4-l 16C on recrystallization from hexane.

The hydrochloride of this compound melts at 2392- 40C.

The 9-( N-acetyl-ethylaminomethyl )-l 2-hydro xy- 9,l0-dihydro-9,IO-ethano-anthracene used as starting material may be prepared thus:

10 Grams of 9-(ethylaminomethyl)-l2-hydroxy- 9, 10-dihydro-9, IO-ethanO-anthracene are acetylated by reaction with 20 ml of acetic anhydride in 40 ml of pyridine at 0C. The whole is evaporated under vacuum and the residue dissolved in chloroform and washed with ZN-hydrochloric acid and with water. Evaporation leaves the amide which melts at 96-98C after recrystallization from ethanol+hexane.

Example 3 l Grams of 9-(benzyliminomethyl)-l2-acetoxy- 9,lO-dihydro-9,lO-ethano-anthracene in 100 ml of tetrahydrofuran are dropped into a suspension of 1.5 g of lithium-aluminum hydride in 50 ml of tetrahydrofuran at room temperature and the whole is boiled for 1 hour and then cooled. ml of water in 10 ml of tetrahydrofuran are added and the precipitate formed is filtered off. The filtrate is evaporated and the residue recrystallized from ethanol+hexane, to yield 9- (benzylaminomethyl)- l 2-hydroxy-9, l0-dihydro-9, l 0- ethano-anthracene of the formula to yield 9-(benzyliminomethyl)-l2-acetoxy-9,l0- dihydro-9, l O-ethano-anthracene melting at l 50-l 5 1C.

Example 4 A solution of 12.0 g of 3-methyl-6',ll,3,4'- tetrahydro-6 l 0-methano-spiro-[ anthracene- 9(10H),5'(2H)[1,3]oxazine] is added dropwise to'a suspension of 4.0 g of lithiumaluminum hydridein 150 ml of tetrahydrofuran and the mixture is then heated at 50C for 2 hours. After cooling to room temperature there are added successively 5 ml of water, 5 ml of sodium hydroxide solution, and 15 ml of water, and the precipitate which forms is filtered off. After cooling, 9- (dimethyl-aminomethyl)- l 2-hydroxy-9, l O-dihydro- 9,10-ethanoanthracene of the formula /CH z-N remains behind which, after being recrystallized from ethanol, melts at l50l54C. The methanesulfonate melts at 2l32l4C.

[ 1,3]oxazine] used as starting material may be prepared thus:

A mixture of l g of 9-(acetylaminomethyl)-l2- hydroxy-9, l 0-dihydro-9, IO-ethano-anthracene, 15 ml of concentrated hydrochloric acid and 15 ml of dioxane is refluxed for 4 hours and then evaporated. The residue is taken up in water and extracted with ether. The aqueous phase is rendered alkaline with sodium hydroxide solution and extracted with chloroform, and evaporated, to yield 9-(aminomethyl)-12-hydroxy- 9,l0-dihydro-9,10-ethano-anthracene which melts at l32l 33C after recrystallization from ether and sublimation. The, hydrochloride melts at 268C.

5.0 g of 9-(aminomethyl)-l2-hydroxy-9,lO-dihydro- 9,10-ethano-anthracene in 50 ml of formic acid are heated at 90C for 2 hours with 4 ml of 30 percent formalin. The reaction mixture is then poured into 300 ml of water and rendered alkaline by the addition. of ml of ION sodium hydroxide solution before it is extracted with methylene chloride. On drying and evaporation of the solvent, 3'-methyl-6,1 1,3, 4-tetrahydro-6, l 0-methano-spiro[ anthracene- 9( lOH),5(2l-l)[ 1,3] -oxazine] of the formula CHa-N I0 is obtained in the form of crystals which melt at l45l 48C. The methanesulfate of this compound melts at 245C.

Example 5 remains behind. After recrystallization from isopropanol the compound melts at l32l35C. The methanesulfonate melts at l68l70C.

The B-( 12-hydroxy-9,lO-dihydro-9, l-ethano-9- anthryl)-propionic acid methylamide used as starting material can be prepared as follows:

A solution of 20 g of l2-acetoxy-9,l0-dihydro-9,l0- ethano-9-anthraldehyde, 9.0 g of cyanoacetic acid ester and 1 ml of piperidine in 100 ml of toluene is boiled for 2 hours, the water formed being separated continuously. On evaporation of the toluene, crystalline ethyl a-cyano-B-( l2-acetoxy-9,l0-dihydro-9, l0- ethano-9-anthryl)-acrylate remains behind which, after recrystallization from alcohol, melts at l45l48C.

22.0 g of this ester are dissolved in 200 ml of dimethylformamide, and the solution treated with 2.0 g of palladium carbon (10 percent), then hydrogenated at room temperature under atmospheric pressure. When the uptake of hydrogen is complete, the catalyst is filtered off, and the filtrate evaporated. Ethyl a-cyano-B- l2-acetoxy-9, l 0-dihydro-9, l 0-ethano-9-anthryl propionate is obtained which, after recrystallization from ethanol, melts at l69l70C.

A solution of 16.0 g of this ester in 100 ml of glacial acetic acid is treated with 50 ml of concentrated hydrochloric acid, then boiled for 12 hours. The batch is then poured into ice-water, and ammonia is added until a basic reaction is achieved. The lactone of B-( 12- hydroxy-9, l 0-dihydro-9, l0-ethano-9-anthryl propionic acid precipitates. After sublimation it melts at 9698C.

15.0 g of this lactone are heated at 120C for 2 hours with 15.0 g of methylamine in 100 ml of ethanol. On evaporation of the solvent, crystalline ,8-( l2-hydroxy- 9, l0-dihydro-9, l0-ethano-9-anthryl )-propionic acid methylamide remains behind, which melts at 22l224C.

Example6 A solution of 9 g of 9-(aminomethyl)-l2-oxo-9,l0- dihydro-9,lO-ethano-anthracene and 9 ml of a 30 percent aqueous solution of formaldehyde in 75 ml of formic acid is heated at 90C for 2 hours. After that, 5N- sodium hydroxide solution is added until an alkaline reaction is achieved, and the batch is then extracted with methylene chloride: After drying and evaporation of the solvent, 9-(dimethylaminomethyl)-l2-0xo-9,10- dihydro-9,IO-ethano-anthracene of the formula /CH3 CHz-N remains behind in the form of crystals of melting point l49l53C. The hydrochloride melts at 238240C.

The 9-(aminomethyl l 2-oxo-9, l0-dihydro-9, l 0- ethanoanthrace'ne used as starting material can be obtained as follows:

dropwise A mixture of 50 g of 9-(aminomethyl)-l2-hydroxy- 9,lO-dihydro-9,IO-ethano-anthracene, 19 g of acetic anhydride and 500 ml of benzene are boiled for 2 hours. On cooling, 9-(acetylaminomethyl)-12-hydroxy- 9,lO-dihydro-9,IO-ethano-anthracene of melting point 165167C separates out.

13 g of chromic acid in 25 ml of water are added to a solution of 50 g of 9- (acetylaminomethyl )-l 2-hydroxy-9, l 0-dihydro-9, l0- ethano-antracene in 500 ml of glacial acetic acid while stirring at room temperature. After 7 hours, 1,200 ml of water and 700 ml of ION-sodium hydroxide solution are added, and the batch is extracted with methylene chloride. After drying and evaporation of the solvent, 9-(acetylaminomethyl)-12-oxo-9,l0-dihydro-9,l0- ethano-anthracene remains behind, which after recrys tallization from ethanol melts at l93l95C.

50.0 g of 9-(acetylaminomethyl)-l2-oxo-9,l0- dihydro-9,IO-ethano-anthracene are boiled for 24 hours at 400 ml of ZN-hydrochloric acid, then filtered hot. When sodium hydroxide solution is added'to the filtrate, a precipitate forms, which is extracted with methylene chloride. On drying and evaporation of the solvent, 9-( aminomethyl l 2-oxo-9, l 0-dihydro-9, l 0- ethano-anthracene remains behind, the hydrochloride of which melts at 268C.

Example 7 5 ml of 30 percent formalin are added to a solution of 48 g of 9-(acetylaminomethyl)-l2-hydroxy-9,l0- dihydro-9,l0-ethanoanthracene in ml of anhydrous formic acid, and the mixture is heated at C for 3 hours. 300 ml of water are then added, and the acid solution extracted with ether. The aqueous phase is separated and rendered alkaline with ION-sodium hydroxide solution, then extracted with methylene chloride. After drying and evaporation of the solvent, crystalline 9-( dimethylaminomethyl l 2-acetoxy-9, l O-dihydro- 9,10-ethano-anthracene of the formula /CH: CHz-N melting at l66169C remains behind.

Example 8 Reduction of ,8-( 12-hydroxy-9,10-dihydro-9, l0- ethan0-9-anthryl)-propionic acid-dimethylamide, B-( l- 2-hydroxy-9, l 0-dihydro-9, l 0-ethano-9-anthryl propionic acid [N'-(B-hydroxyethyl)-piperazide], B-( l2-hydroxy-9, l0-dihydro-9, l 0-ethano-9-anthryl propionic acid morpholide, B-( l2-hydroxy-9,l0- dihydro-9, l0-ethano-9-anthryl )-propionic acidpyrrolidide or ,B-( 12-hydroxy-9,10-dihydro-9, l0- ethano-9-anthryl)-propionic acid-piperidide with lithium aluminum hydride in a manner analogous to that described in Example leads to 9-(7- dimethylaminopropyl l 2-hydroxy-9, l O-dihydro-9, l 0- ethano-anthracene, 9-[y-(N-[B-hydroxyethyl]- piperazino )-propyl]- l 2-hydroxy-9, l O-dihydro-9, ethano-anthracene, 9-( 'y-morpholinopropyl l 2- hydroxy-9, l 0-dihydro-9, IO-ethanO-anthracene, 9-(ypyrrolidinopropyl)-l2-hydroxy-9,lO-dihydro-9,10- ethano-anthracene, or 9-(y-piperidinopropyl)-l2- hydroxy-9, l O-dihydro-9, l O-ethano-anthracene, respectively, and salts thereof, such as the hydrochlorides or methanesulfonates.

, Example 9 Hydrolysis of 9-[y-(N-acetyl-methylamino)-propyl]- l2-oxo-9, l O-dihydro-9, IO-ethano-anthracene, 9-(N- acetyl-ethylaminomethyl)-12-oxo-9,l0dihydro-9,l0- ethano-anth racene or 9-( N-acetylbenzylaminomethyl )-l 2-oxo-9, l 0-dihydro-9, l 0- ethano-anthracene with hydrochloric acid, for example, analogous to the hydrolysis of the 9-(acetylaminomethyl)- l 2-oxo compound described in Example 6, leads to 9-('y-methylaminopropyl)-l2-oxo-9,10- dihydro-9, l O-ethano-anthracene, (ethylaminomethyl)- l 2-oxo-9,l0-dihydro-9, 10- ethano-anthracene, or 9-(benzylaminomethyl)- l 2-oxo- 9,10-dihydro-9, IO-ethano-anthracene, respectively, and salts thereof, such as the hydrochlorides or methanesulfonates.

Example 10 performed catalytically, 9-(cyclopropylaminomethyl)- l 2-acetoxy-9, l0-dihydro-9, l O-ethanoanthracene is obtained or a salt thereof, such as the hydrochloride or methanesulfonate.

Example 11 By reacting 9-(dimethylaminomethyl)-l2-oxo-9,l0-

' dihydro-9,lO-ethano-anthracene with methyl magnesium bromide in tetrahydrofuran and destroying the magnesium halide compound with water, 9- (dimethylaminomethyD-l 2-methyll 2-hydroxy-9, l 0- dihydro-9,lO-ethano-anthracene can be obtained or a salt thereof, such as the hydrochloride or the methanesulfonate.

Example 12 Methylation of 9-('y-methylaminopropyl)-l2-oxo- 9, l 0-dihydro-9, l O-ethano-anthracene or 2,6-dichloro- 9-( aminomethyl l 2-oxo-9, l 0-dihydro-9, l O-ethanoanthracene with formaldehyde and formic acid in a manner analogous to that described in Example 6, leads to 9-(y-dimethylaminopropyl l 2-oxo-9, l 0- dihydro-9,IO-ethano-anthraCene, or 2,6-dichloro-9- (dimethylaminomethyl l 2-oxo-9, 10-dihydro-9, l 0- ethano-anthracene, respectively, or salts thereof, such as the hydrochloride or methanesulfonate.

Example 13 By reduction of 2,6-dichloro-3'-methyl-6'-l l,3',4'- tetrahydro-6, l O-methano-spiro[anthracene- 9( l0l-l),5(2'H)[ l,3]oxazine] with lithium-aluminum hydride in a manner analogous to that described in Example 4, it is possible to obtain 2,6-dichloro-9- (dimethylaminomethyl l 2-hydroxy-9, 1 O-dihydro- 9,10-ethano-anthracene and its salts, such as the hydrochloride or the methanesulfonate.

The 2,6-dichloro-3'-methyl-6',l 1,3 ,4'- tetrahydro6,l0-methano-spiro[anthracene- 9(10H),5(2H)[1,3]oxazine] used as starting material can be obtained in a manner analogous to that described iti Example 4 by reacting 2,6-dichloro-9- (aminomethyl l 2-hydroxy-,lO-dihydro-9, I O-ethanoanthracene with formic acid and 30 percent formalin. It can be converted in the usual manner into salts, for example the hydrochloride or the methanesulfonate.

Example 14 By oxidizing 1 9-(diethylaminomethyl)-l2-hydroxy- 9,lO-dihydro-9,lO-ethanoantracene it is possible to obtain 9-(diethylaminomethyl)-l 2-oxo-9,10-dihydro- 9,10-ethanoanthracene and its salts, for example the hydrochloride or the methanesulfonate.

Example 15 Tablets, each containing 25 mg of active substance, can be prepared, for example, from the-following ingredients:

m 9-(dimcthylaminomethyU-l2-acetoxy-9.l0-dihydro- 25 g 9,10-ethano-anthracene hydrochloride lactose 35 wheat starch 44.4 colloidal silicic acid 6 magnesium stearate 0.6 fhlc In an analogous manner, tablets containing 3- methyl-6,l l ,3 ',4-tetrahydro-6, l O-methanospiro[anthraeene-9( 10H ),5-(2'H)[ 1,3]oxazine] methanesulfonate or 9-(diethylaminomethyl)-l2- hydroxy-9 l 0-dihydro-9, l O-ethano-anthraeene hyd rochloride can be made.

We claim:

1. A member selected from the group consisting of compounds of the formula in which R is a member selected from the group consisting of hydrogen and methyl, R and R, each stands for a member selected from the group consisting of hydrogen and lower alkyl, R and R, each represents a member selected from the group consisting of hydrogen and lower alkyl and, when taken together, lower alkylene, R stands for a member selected from the group consisting of hydrogen, lower oxaalkyl, lower alkyl, lower cycloalkyl and phenyl-lower alkyl, and R R R and R each stands for a member selected from pounds of the formula in which R, stands for a member selected from the group consisting of hydrogen, lower alkyl, and benzyl, R and R each representsa member selected from the group consisting of hydrogen and lower alkyl, and R and R each represents a member selected from the group consisting of hydrogen, methoxy and chlorine,

and their acid addition salts. 

2. A product as claimed in claim 1 which product is 3''-methyl-6'',11,3'',4''-tetrahydro-6'',10-methano-spiro(anthracene-9(10H), 5''(2''H)(1,3)oxazine) or an acid addition salt thereof.
 3. A product as claimed in claim 1 which product is 2,6-dichloro-3''-methyl-6'',11,3'',4''-tetrahydro-6'',10-methanospiro(anthracene -9(10H),5''(2''H)(1,3)oxazine) or an acid addition salt thereof.
 4. A product as claimed in claim 1 which product is a member selected from the group consisting of compounds of the formula 